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Scand J Caring Sci; 2010; 24; 755-763 The aim was to test sampling and explore sample characteristics in a pilot study using a case management intervention for older people with functional dependency and repeated contact with the healthcare services as well as to investigate the effects of the intervention on perceived health and depressed mood after 3 months. The aim was also to explore internal consistency in the life satisfaction index Z, activities of daily living-staircase and Geriatric Depression Scale-20. This pilot study was carried out in a randomised controlled design with repeated follow-ups. In all, 46 people were consecutively and randomly assigned to either an intervention (n = 23) or a control (n = 23) group. Two nurses worked as case managers and carried out the intervention, which consisted of four parts. No differences were found between the groups at baseline. The results showed the participants had low life satisfaction (median 14 vs. 12), several health complaints (median 11) and a high score on the Geriatric Depression Scale (median 6) at baseline, indicating the risk of depression. No significant effects were observed regarding depressed mood or perceived health between or within groups at follow-up after 3 months. Cronbach′s alpha showed satisfactory internal consistency for group comparisons. The sampling procedure led to similar groups. The life satisfaction, functional dependency and symptoms of depression measures were reliable to use. No changes in perceived health and symptoms of depression were found after 3 months, indicating that it may be too early to expect effects. The low depression score is noteworthy and requires further research. [ABSTRACT FROM AUTHOR]

This study explored frail older adults' overall experience of receiving health care and/or social services. Frail older adults with unstable health are dependent on the health care system because of the frequency of their contacts with it. More knowledge is needed about how they experience the health care and social services they receive. Interviews with 14 older adults (mean age = 81) revealed one main category, Having Power or Being Powerless, that incorporated three categories: Autonomous or Without Control in Relation to the Health Care and/or Social Services System, Being Confirmed or Violated in Relation to Caregivers, and Paradoxes in Health Care or Social Services. Each category comprised subcategories reflecting aspects of having power or being powerless. The findings indicate it is important for health care and social services to ensure a high level of interpersonal continuity to empower frail older adults. This may contribute to more relationship-based care and help older adults remain in control of their life situations. [ABSTRACT FROM AUTHOR]

PURPOSE: The aim of this study was to describe elderly patients' knowledge about and attitudes towards their medicines in Swedish primary care. METHODS: Thirty-four patients aged 65 years and above with multiple illnesses were included. Medication knowledge was assessed with a questionnaire measuring knowledge about indication and possible adverse effects for each medicine. Attitudes were investigated with the Beliefs about Medicines Questionnaire. RESULTS: The indication of at least 75% of their medicines was known to 71% of the patients. Patients with polypharmacy and multi-dose drug distribution respectively had significantly less knowledge. Eighty-four percent had no knowledge about possible adverse effects. For 93% of the patients, the benefits of the medication outweighed the costs (concerns). No correlation was found between attitudes and knowledge. CONCLUSIONS: The knowledge about indication was higher than previously seen, but the knowledge about possible adverse effects was poor. The patients had strong beliefs in the benefits of their medication. [ABSTRACT FROM AUTHOR]

AIMS AND OBJECTIVES: The aim was to study the association between gender, extent and content of care, satisfaction, coping and difficulties in the caregiving situation among older (75+) caregivers and to identify clusters of caregivers. The aim was also to explore psychometrically two instruments assessing satisfaction and difficulties in family caregivers. BACKGROUND: Caregiving is a complicated phenomenon. Much of the research has focused on negative aspects, such as the burden, stress and emotional strain. Caregiving is known to affect health negatively for the caregivers. Little is known about satisfaction and motivation in voluntary work, such as informal caregiving, especially among older persons. DESIGN AND METHODS: Cross-sectional. The sample for this study consisted of 171 informal caregivers aged 75 and over, identified from an age-stratified sample in a postal survey among older people in the southern part of Sweden. RESULTS: Male caregivers proved to be more satisfied than female caregivers; caregiving had seemingly widened their horizon and had helped them to grow as persons. Based on satisfaction scores, those satisfied had a higher proportion of male caregivers and a significantly higher amount of caregiving hours per week. They used other coping strategies than the respondents in the other cluster, i.e. less satisfied in using more problem-solving strategies. CONCLUSIONS: The instruments tested were appropriate for work in clinical and research settings, although the internal dropout indicates that a shorter version would be more useful. Those who found satisfaction in care used more problem-focused coping strategies and were more often men than women. From a salutogenic point of view, this may give important knowledge about factors that can promote health. The findings indicate that women deserve extra attention as informal caregivers as they did not find caregiving as rewarding as the men did. This may in turn make them less protected against the negative consequences of caregiving. RELEVANCE TO CLINICAL PRACTICE: Reinforcing the health-promoting qualities in caregivers who are not feeling well, with women as a particularly vulnerable group, may restrict unnecessary suffering for both the caregiver and the person cared for. [ABSTRACT FROM AUTHOR]

AIM: This paper reports a study to investigate coping strategies and sense of coherence in relation to gender, the extent of care, caregiving activities and health-related quality of life in a population-based sample of caregivers aged 75 and over. BACKGROUND: Caring for another person can be stressful both emotionally, and caregiver burden may affect quality of life in a negative way for the carer. Caregivers' experience of burden may depend on for example, the behaviour of the person cared for, their own health and their sense of coherence. Older people take a great part of caregiving responsibility and thus understanding of their strain and coping is required. METHODS: A postal survey was carried out in 2001 with 171 informal caregivers, aged 75 or older. The response rate was 47%. The questionnaire included the Short-Form 12, Carer's Assessment of Managing Index, and Sense of Coherence instrument. RESULTS: Almost 70% of caregivers provided help every day. Higher health-related quality of life was predicted by using self-sustaining coping strategies and by high sense of coherence. Poor economic situation and demanding social and practical support predicted low scores. CONCLUSION: These findings could help identify those at risk of low quality of life due to caregiving, dysfunctional coping or lack of information about care. Early intervention, including education about alternative coping strategies and practical information, might allow caregivers better possibilities to continue caring with less negative effects on their lives. [ABSTRACT FROM AUTHOR]

AIM: This paper reports a study investigating quality of life in relation to loneliness, caregiving, social network, gender, age and economic status among caregiving men and women in a population-based sample aged 75 years or older. BACKGROUND: Because of demographic changes, in the future more care for older people will be given by informal caregivers who are themselves older. Being old and caring for another older person may affect various aspects of life, such as physical and emotional health and decreased time for respite, which may affect social life and quality of life. METHOD: A postal questionnaire including the Short Form Health Survey was used. The sample consisted of 4278 people, aged 75 years and over, living in Sweden. Of these, 783 (18%) were caregivers. FINDINGS: Caregivers had a larger social network and reported feelings of loneliness less often than non-caregivers. Forty per cent of caregivers helped every day. There were gender differences in experiences of loneliness during the last year, with the frequency of intense feelings of loneliness being higher among women. Loneliness and a small or non-existent network were significantly associated with low quality of life among caregivers, as well as in the total sample. The results showed significant association between loneliness, weak social network and low mental quality of life. CONCLUSIONS: The fact that loneliness was the most important factor predicting low quality of life among caregivers, as well as older people in general, indicates that it is crucial in the care of older people. From a nursing perspective, the findings indicate the advantage of helping older people to keep up and develop their social networks. Nursing care should involve steps to maintain the social network before an older person becomes too weak, since decreased health status makes social contacts more difficult. [ABSTRACT FROM AUTHOR]

Objective: The high prevalence of osteoporosis in rheumatoid arthritis (RA) is due to inflammation that stimulates differentiation of osteoclasts, a process involving circulating monocytes and T cell-derived factors. The aim of this study was to evaluate relations between circulating monocytes, T cell subsets, and changes in bone characteristics before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in RA., Methods: Thirty patients with untreated early RA who met the American College of Rheumatology/EULAR 2010 criteria were included. Data were collected before and 48 weeks after treatment with methotrexate (MTX) together with one of three bDMARDs (abatacept, tocilizumab, or certolizumab pegol). Disease activity was measured using the Clinical Disease Activity Index, swollen or tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates. Proportions of monocyte and CD4 + T cell subsets in blood samples were analyzed by flow cytometry. Bone densitometry was performed using high-resolution peripheral quantitative computed tomography (HR-pQCT)., Results: HR-pQCT revealed an overall decrease in cortical (P = 0.009) and trabecular (P = 0.034) bone mineral density, although a subset of patients showed no bone loss after 48 weeks of treatment. The overall bone loss was not associated with age, body mass index, sex, intraarticular glucocorticoid injections, or baseline disease activity. Loss of trabecular bone volume fraction correlated with high proportions of circulating CXCR3 + Th2 cells (r = -0.38, P = 0.04) and CXCR3 + Th17 cells (r = -0.36, P = 0.05) at baseline. Similarly, no loss of trabecular bone volume fraction correlated with high proportions of regulatory T cells (r = 0.4, P = 0.03) at baseline. However, the associations were not significant when corrected for confounders and multiple testing., Conclusion: MTX together with bDMARDs efficiently reduce disease activity but only prevent bone loss in a subset of patients with RA after 48 weeks of treatment. The correlations of circulating baseline T helper cell and regulatory T cell populations with trabecular bone changes suggest a potential novel role for these cells in systemic bone homeostasis during early RA., (© 2024 The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Subsets of CD21 -/low memory B cells (MBCs), including double-negative (DN, CD27 - IgD - ) and Tbet + CD11c + cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21 -/low MBCs correlate with joint destruction. However, whether this is due to the Tbet + CD11c + subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21 -/low Tbet + CD11c + MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA)., Methods: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet + CD11c + MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet + CD11c + B cells with T cells was used to assess costimulatory capacity., Results: CD21 -/low Tbet + CD11c + MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet + CD11c + MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet + CD11c + B cells induced retinoic acid receptor-related orphan nuclear receptor γT expression in CD4 + T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction., Conclusion: This study suggests that Tbet + CD11c + MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Polymer-based nanoparticles (NPs) that react to altered physiological characteristics have the potential to enhance the delivery of therapeutics to a specific area. These materials can utilize biochemical triggers, such as low pH, which is prone to happen locally in an inflammatory microenvironment due to increased cellular activity. This reduced pH is neutralized when inflammation subsides. For precise delivery of therapeutics to match this dynamic reaction, drug delivery systems (DDS) need to not only release the drug (ON) but also stop the release (OFF) autonomously. In this study, we use a systematic approach to optimize the composition of acetalated dextran (AcDex) NPs to start (ON) and stop (OFF) releasing model cargo, depending on local pH changes. By mixing ratios of AcDex polymers (mixed NPs), we achieved a highly sensitive material that was able to rapidly release cargo when going from pH 7.4 to pH 6.0. At the same time, the mix also offered a stable composition that enabled a rapid ON/OFF/ON/OFF switching within this narrow pH range in only 90 min. These mixed NPs were also sensitive to biological pH changes, with increased release in the presence of inflammatory cells compared to healthy cells. Such precise and controllable characteristics of a DDS position mixed NPs as a potential treatment platform to inhibit disease flare-ups, reducing both systemic and local side effects to offer a superior treatment option for inflammation compared to conventional systems.

Background: The use of remote services such as video consultations (VCs) has increased significantly in the wake of the COVID-19 pandemic. In Sweden, private healthcare providers offering VCs have grown substantially since 2016 and have been controversial. Few studies have focused on physicians' experiences providing care in this context. Our aim was to study physicians' experiences of VCs, focusing on the work environment, quality of care, and educational needs., Methods: Twenty-two semi-structured interviews were performed with physicians working with VCs in Sweden, and analyzed through inductive content analysis., Results: We identified five categories; flexibility, social work environment, impact on care and society, continuous learning and career development, and organizational support. Flexibility and accessibility were considered positive features of working digitally by giving physicians control over their time and workplace and increasing patients' timely access to healthcare. Regarding collegial contact and social activities in a digital context, the majority of the participants did not experience any significant difference compared to the physical context. Access to technical support services, educational support, and collegial support in decision-making, guidance, and consultations were described as well-functioning. Satisfied patients positively impacted the work environment, and participants felt that VCs have a positive socio-economic effect. Continuity of care was considered supported, but patients did not always prioritize this. Privacy risks were considered a challenge, as were poor development of clinical skills due to the low variation of patient cases. Working for an online healthcare provider was contributing to career advancements for junior clinicians., Conclusions: Physicians appreciate the flexibility of the digital context and seem satisfied with a work environment where they have a high level of control, but few consider this a full-time career option. The pandemic year 2020 has led to a significant increase in the implementation of VCs in traditional care systems. How this affects the work environment and continuous education needs and career development remains to be seen., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints., Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE)., Results: Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE., Conclusion: A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Drug delivery strategies for joint diseases need to overcome the negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to increase uptake efficiency by harnessing the anionic charge of the cartilage but have neglected to address potential interactions with the protein-rich biological environment of the joint space. We aimed to evaluate the effects of hard protein coronas derived from osteoarthritis (OA) and rheumatoid arthritis (RA) patient synovial fluids as well as the commonly used fetal calf serum (FCS) on nanoparticle (NP) uptake into tissues and cells., Methods: We developed a NP panel with varying PEGylation and incubated them with synovial fluid from either OA, RA patients or FCS. We evaluated the effects of the formed NP-biocorona complex uptake into the porcine articular cartilage explants, chondrocytes and monocyte cell lines and primary patient FLS cells. Proteins composing hard biocoronas were identified using a quantitative proteomics approach., Results: Formed biocoronas majorly impacted NP uptake into cartilage tissue and dictated their uptake in chondrocytes and monocytes. The most suitable NP for potential OA applications was identified. A variety of proteins that were found on all NPs, irrespective of surface modifications. NP-, and protein-specific differences were also observed between the groups, and candidate proteins were identified that could account for the observed differences., Conclusions: This study demonstrates the impact of protein coronas from OA and RA patient synovial fluids on NP uptake into cartilage, emphasizing the importance of biological microenvironment considerations for successful translation of drug delivery vehicles into clinics., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Treatment with CTLA-4Ig blocks T-cell activation and is clinically effective in RA. However, it is unknown if specific CD4+ T-cell subsets in blood at baseline predict remission after CTLA-4Ig, or other biological treatments with different modes of action, and how treatment affects CD4+ T cells in patients with untreated early RA (eRA)., Methods: This study included 60 patients with untreated eRA from a larger randomized trial. They were treated with methotrexate combined with CTLA-4Ig (abatacept, n = 17), anti-IL6 receptor (tocilizumab, n = 21) or anti-TNF (certolizumab-pegol, n = 22). Disease activity was assessed by clinical disease activity index (CDAI), DAS28, swollen joint counts, tender joint counts, CRP and ESR. The primary outcome was CDAI remission (CDAI ≤ 2.8) at week 24. Proportions of 12 CD4+ T-cell subsets were measured by flow cytometry at baseline and after 4, 12 and 24 weeks of treatment., Results: In patients treated with CTLA-4Ig, the proportions of PD-1+TFh and CTLA-4+ conventional CD4+ T cells at baseline predicted CDAI remission at week 24. CD4+ T-cell subset proportions could not predict remission after treatment with anti-IL6R or anti-TNF. The percentage of regulatory T cells (Tregs) expressing CTLA-4 decreased in all treatment arms by 24 weeks, but only CTLA-4Ig treatment significantly reduced the proportions of Tregs and PD-1+T follicular helper (TFh) cells., Conclusion: These findings indicate that circulating proportions PD-1+TFh and CTLA-4+ conventional CD4+ T cells at baseline may serve as predictive biomarkers for remission in early RA after CTLA-4Ig treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Women with SLE face an increased risk of adverse pregnancy outcomes compared with healthy women, but the underlying immunological mechanisms are unknown. Given the recognised association of neutrophil activation with SLE pathogenesis, we examined whether there is increased neutrophil activation and inflammation in blood and placenta in SLE relative to healthy pregnancy., Methods: At delivery, peripheral blood, maternal-derived intervillous blood and placentas were collected from 12 SLE and 10 healthy control pregnancies. The proportion of low-density granulocytes (LDGs) and the activation status of LDG and normal-density granulocytes were examined with flow cytometry. The chemokines CXCL8 and CXCL1 were quantified with a cytometric bead-based assay and interferon alpha (IFNα) protein levels with a Simoa method. IFNα-stimulated maternal-derived decidual stromal cells were examined for CXCL8 gene expression with qPCR. A pathologist, blinded to the patient background, examined all placentas., Results: Women with SLE had significantly higher proportions of LDG in peripheral blood compared with controls (p=0.02), and LDG in both peripheral and intervillous blood were more activated in SLE relative to healthy pregnancies (peripheral blood: p=0.002 and intervillous blood: p=0.05). There were higher levels of CXCL8 and CXCL1 in intervillous compared with peripheral blood in women with SLE (p=0.004 and p=<0.0001, respectively) but not in controls. In SLE pregnancy, IFNα was detectable in 6 out of 10 intervillous blood samples but only in one control. Stimulation with IFNα upregulated CXCL8 gene expression in decidual stromal cells from both SLE and healthy pregnancy. Histological chorioamnionitis was present in 6 out of 12 placentas from women with SLE and in 1 out of 10 controls., Conclusions: In women with SLE, locally produced chemokines in the placenta are increased and may attract and activate neutrophils. This in turn could contribute to placental inflammation and dysfunction and increased risk of placenta-related pregnancy complications., Competing Interests: Competing interests: Unrelated to this work, HZ declares that he has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Unrelated to this work, KB declares that he has served as a consultant, at advisory boards or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Unrelated to this work, A-KE declares that she has received consulting fees from AbbVie and Pfizer. The remaining authors report no conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To illuminate patients' experiences of being hospitalised in a hospital with a single-bed room design., Introduction: Many patients seem to prefer single-bed hospital rooms. However, studies have also shown that patients do see the advantages of multiple-bed rooms., Method: Interviews were conducted with 16 inpatients from a surgical ward in a hospital building with a single-bed room design. A hermeneutical-phenomenological approach guided by van Manen's four life-world existentials was used to analyse the interviews., Results: The essential meaning was that patients felt secure because they could create a personal environment without disruptive elements. The room was private, and this implied feelings of homeliness, which allowed patients to focus on themselves and was thought to facilitate the recovery process. The patients preferred staying in their room, and the relationship with the personnel was central. Feelings of loneliness and isolation could occur and could be frightening. Being hospitalised in a single-bed room meant balancing between feeling secure and feeling insecure. The following four themes emerged: A homely environment, The need for company and security, Time as unpredictable and involving waiting and Focus on healing the body., Conclusion: Patients experienced that a single-bed room allowed them to focus on their recovery, have visitors without disturbing others and create a feeling of homeliness. However, mobilisation is not a natural part of the recovery process when patients have all they need in their rooms. The patients' need for social interaction and confirmation was not satisfied without effort and planning on the part of staff., (© 2014 Nordic College of Caring Science.)

Objective: Fibroblast-like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different "omics" data sets, i.e., 1) risk genes in RA, 2) differentially expressed genes, and 3) differential DNA methylation in RA versus osteoarthritis (OA) FLS, we identified LBH (limb bud and heart development) as a candidate gene in RA. The present study was undertaken to define the role of this gene in FLS., Methods: Synovial tissue specimens from RA and OA patients were collected at the time of joint replacement surgery. LBH expression was silenced using small interfering RNA or overexpressed using an LBH expression vector in primary FLS. Gene expression profiles were determined by microarray and assessed using Ingenuity Pathway Analysis. Effects of modified LBH expression were investigated in functional assays., Results: LBH was expressed in the synovial lining layer in patients with RA. Transforming growth factor β1 significantly increased LBH expression in primary FLS, and platelet-derived growth factor BB decreased it. Pathway analysis of the transcriptome of LBH-deficient FLS compared to control FLS identified "cellular growth and proliferation" as the most significantly enriched pathway. In growth assays, LBH deficiency increased FLS proliferation. Conversely, LBH overexpression significantly inhibited cell growth. Cell cycle analysis demonstrated a marked increase in cells entering the cell cycle in LBH-deficient FLS compared to controls. LBH did not alter apoptosis., Conclusion: LBH is a candidate gene for synovial pathology in RA. It is regulated by growth factors and modulates cell growth in primary FLS. Our data suggest a novel mechanism for synovial intimal hyperplasia and joint damage in RA., (© 2015, American College of Rheumatology.)

The lubricative, heavily glycosylated mucin-like synovial glycoprotein lubricin has previously been observed to contain glycosylation changes related to rheumatoid and osteoarthritis. Thus, a site-specific investigation of the glycosylation of lubricin was undertaken, in order to further understand the pathological mechanisms involved in these diseases. Lubricin contains an serine/threonine/proline (STP)-rich domain composed of imperfect tandem repeats (EPAPTTPK), the target for O-glycosylation. In this study, using a liquid chromatography-tandem mass spectrometry approach, employing both collision-induced and electron-transfer dissociation fragmentation methods, we identified 185 O-glycopeptides within the STP-rich domain of human synovial lubricin. This showed that adjacent threonine residues within the central STP-rich region could be simultaneously and/or individually glycosylated. In addition to core 1 structures responsible for biolubrication, core 2 O-glycopeptides were also identified, indicating that lubricin glycosylation may have other roles. Investigation of the expression of polypeptide N-acetylgalactosaminyltransferase genes was carried out using cultured primary fibroblast-like synoviocytes, a cell type that expresses lubricin in vivo. This analysis showed high mRNA expression levels of the less understood polypeptide N-acetylgalactosaminyltransferase 15 and 5 in addition to the ubiquitously expressed polypeptide N-acetylgalactosaminyltransferase 1 and 2 genes. This suggests that there is a unique combination of transferase genes important for the O-glycosylation of lubricin. The site-specific glycopeptide analysis covered 82% of the protein sequence and showed that lubricin glycosylation displays both micro- and macroheterogeneity. The density of glycosylation was shown to be high: 168 sites of O-glycosylation, predominately sialylated, were identified. These glycosylation sites were focused in the central STP-rich region, giving the domain a negative charge. The more positively charged lysine and arginine residues in the N and C termini suggest that synovial lubricin exists as an amphoteric molecule. The identification of these unique properties of lubricin may provide insight into the important low-friction lubricating functions of lubricin during natural joint movement., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Fms-like tyrosine kinase 3 ligand (Flt3L) is known as the primary differentiation and survival factor for dendritic cells (DCs). Furthermore, Flt3L is involved in the homeostatic feedback loop between DCs and regulatory T cell (Treg). We have previously shown that Flt3L accumulates in the synovial fluid in rheumatoid arthritis (RA) and that local exposure to Flt3L aggravates arthritis in mice, suggesting a possible involvement in RA pathogenesis. In the present study we investigated the role of Flt3L on DC populations, Tregs as well as inflammatory responses in experimental antigen-induced arthritis. Arthritis was induced in mBSA-immunized mice by local knee injection of mBSA and Flt3L was provided by daily intraperitoneal injections. Flow cytometry analysis of spleen and lymph nodes revealed an increased formation of DCs and subsequently Tregs in mice treated with Flt3L. Flt3L-treatment was also associated with a reduced production of mBSA specific antibodies and reduced levels of the pro-inflammatory cytokines IL-6 and TNF-α. Morphological evaluation of mBSA injected joints revealed reduced joint destruction in Flt3L treated mice. The role of DCs in mBSA arthritis was further challenged in an adoptive transfer experiment. Transfer of DCs in combination with T-cells from mBSA immunized mice, predisposed naïve recipients for arthritis and production of mBSA specific antibodies. We provide experimental evidence that Flt3L has potent immunoregulatory properties. Flt3L facilitates formation of Treg cells and by this mechanism reduces severity of antigen-induced arthritis in mice. We suggest that high systemic levels of Flt3L have potential to modulate autoreactivity and autoimmunity.

Background: The increasing need for long-term care as well as diminished financial resources may compromise the quality of care of older people. Thus the need for clinically based quality of care monitoring to guide development of long-term services has been pointed out., Objectives: The aim of this study was to investigate trends in quality of care during 2003-2009 as reflected in the Minimum Data Set quality indicator outcome in Icelandic nursing homes and to investigate the association of Minimum Data Set quality indicators with residents' health status (health stability, pain, depression and cognitive performance) and functional profile (activities of daily living and social engagement)., Design: Retrospective analysis of nursing home data over 7 years., Methods: The sample used for analysis was 11,034 Minimum Data Set assessments of 3694 residents living in Icelandic nursing homes in 2003-2009. Minimum Data Set quality indicators were used to measure quality of care. The chi-square test for trend and multivariate logistic regression were used to analyse the data., Results: The mean age of residents during the period of the study ranged from 82.3 (SD 9.1) to 85.1 (SD 8.3) and women accounted for from 65.2% to 67.8%. Findings for 16 out of 20 quality indicators indicated a decline in quality of care (p<0.05), although in 12 out of 20 indicators the prevalence was lower than 25%. One quality indicator showed improvement, i.e. for "Bladder and bowel incontinence without a toileting plan" from 17.4% in 2003 decreasing to 11.5% in 2009 (p<0.001). Residents' health and functional status partially explain the increased prevalence of the quality indicators over time., Conclusion: Further developments in quality of care in Icelandic nursing homes need to be monitored as well as the association between residents' health and functional status and the Minimum Data Set quality indicator outcome. The areas of care where the Minimum Data Set quality indicators showed need for improvement included treatment of depression, number of medications, resident activity level and behavioural symptoms., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Lubricin (or proteoglycan 4 (PRG4)) is an abundant mucin-like glycoprotein in synovial fluid (SF) and a major component responsible for joint lubrication. In this study, it was shown that O-linked core 2 oligosaccharides (Galβ1-3(GlcNAcβ1-6)GalNAcα1-Thr/Ser) on lubricin isolated from rheumatoid arthritis SF contained both sulfate and fucose residues, and SF lubricin was capable of binding to recombinant L-selectin in a glycosylation-dependent manner. Using resting human polymorphonuclear granulocytes (PMN) from peripheral blood, confocal microscopy showed that lubricin coated circulating PMN and that it partly co-localized with L-selectin expressed by these cells. In agreement with this, activation-induced shedding of L-selectin also mediated decreased lubricin binding to PMN. It was also found that PMN recruited to inflamed synovial area and fluid in rheumatoid arthritis patients kept a coat of lubricin. These observations suggest that lubricin is able to bind to PMN via an L-selectin-dependent and -independent manner and may play a role in PMN-mediated inflammation.

Background: The knowledge over time of the health status and changes in care needs of newly admitted nursing home residents is limited., Objectives: To investigate trends in residents' health status and functional profile at admission to nursing homes and compare rural and capital areas in Iceland over an 11-year period., Design: Retrospective analysis of nursing home data over 11 years (1996-2006)., Participants: Residents, who had been assessed with the Minimum Data Set assessment within 90 days from admittance (n = 2206)., Method: Non-parametric tests for descriptive statistics and linear regressions were used to analyse time trends., Results: The mean age ranged from 80.1 to 82.8, and women accounted for 52.7% to 67.1%. The level of independency indicated intact cognitive performance in 28.6-61.4% and in 42.5-68% in activities of daily living performance. A weak, but significant, linear trend was seen in residents' health becoming less stable, their cognitive performance improving, more pain being reported and greater participation in social activities over the 11 years., Conclusion: Some residents might have stayed at home longer had they been given appropriate home care and the opportunity of rehabilitation. Pain management and social activities are areas where more staff knowledge seems to be needed., Implications for Practice: Resources to enable old people to remain at home need to be explored before their entry into nursing homes. Whereas providing services at the appropriate level is important for society as well as older people., (© 2011 Blackwell Publishing Ltd.)

A modified Delphi method was used to determine thresholds for Minimum Data Set quality indicators for Icelandic nursing homes. The thresholds were then applied to quality outcomes in Icelandic nursing homes for the year 2009. The thresholds indicate areas of good or poor care and can be used for planning services. Icelandic nursing homes seem to be doing best in incontinence and nutritional care. However, improvement is needed in care practices for depression, medication, and activity.

Objective: Human resistin has proinflammatory properties that activate NF-κB-dependent pathways, whereas its murine counterpart is associated with insulin resistance. The aim of this study was to examine potential cross-talk between resistin and insulin/insulin-like growth factor (IGF) signaling in rheumatoid arthritis (RA)., Methods: Levels of IGF-1, IGF binding protein 3, and resistin were measured in the blood and synovial fluid of 60 patients with RA and 39 healthy control subjects. Human RA synovium was implanted subcutaneously into SCID mice, and the mice were treated with resistin-targeting small interfering RNA. Primary synovial fibroblasts from patients with RA, as well as those from patients with osteoarthritis, and the human fibroblast cell line MRC-5 were stimulated with resistin. Changes in the IGF-1 receptor (IGF-1R) signaling pathway were evaluated using histologic analysis, immunohistochemistry, and reverse transcription-polymerase chain reaction., Results: Resistin and IGF-1R showed different expression profiles in RA synovia. Low levels of IGF-1 in RA synovial fluid were associated with systemic inflammation and inversely related to the levels of resistin. Stimulation of synovial fibroblasts with resistin induced phosphorylation of IGF-1R to a degree similar to that with insulin, and also induced phosphorylation of transcription factor Akt. This was followed by gene expression of GLUT1, IRS1, GSK3B, and the Akt inhibitors PTPN and PTEN. Abrogation of resistin expression in vivo reduced the expression of IGF-1R, the phosphorylation of Akt, and the expression of PTPN and PTEN messenger RNA in RA synovium implanted into SCID mice., Conclusion: Resistin utilizes the IGF-1R pathway in RA synovia. Abrogation of resistin synthesis in the RA synovium in vivo leads to reductions in the expression of IGF-1R and level of phosphorylation of Akt., (Copyright © 2011 by the American College of Rheumatology.)

Background: An increasing numbers of deaths occur in nursing homes. Knowledge of the course of development over the years in death rates and predictors of mortality is important for officials responsible for organizing care to be able to ensure that staff is knowledgeable in the areas of care needed. The aim of this study was to investigate the time from residents' admission to Icelandic nursing homes to death and the predictive power of demographic variables, health status (health stability, pain, depression and cognitive performance) and functional profile (ADL and social engagement) for 3-year mortality in yearly cohorts from 1996-2006., Methods: The samples consisted of residents (N = 2206) admitted to nursing homes in Iceland in 1996-2006, who were assessed once at baseline with a Minimum Data Set (MDS) within 90 days of their admittance to the nursing home. The follow-up time for survival of each cohort was 36 months from admission. Based on Kaplan-Meier analysis (log rank test) and non-parametric correlation analyses (Spearman's rho), variables associated with survival time with a p-value < 0.05 were entered into a multivariate Cox regression model., Results: The median survival time was 31 months, and no significant difference was detected in the mortality rate between cohorts. Age, gender (HR 1.52), place admitted from (HR 1.27), ADL functioning (HR 1.33-1.80), health stability (HR 1.61-16.12) and ability to engage in social activities (HR 1.51-1.65) were significant predictors of mortality. A total of 28.8% of residents died within a year, 43.4% within two years and 53.1% of the residents died within 3 years., Conclusion: It is noteworthy that despite financial constraints, the mortality rate did not change over the study period. Health stability was a strong predictor of mortality, in addition to ADL performance. Considering these variables is thus valuable when deciding on the type of service an elderly person needs. The mortality rate showed that more than 50% died within 3 years, and almost a third of the residents may have needed palliative care within a year of admission. Considering the short survival time from admission, it seems relevant that staff is trained in providing palliative care as much as restorative care.

Introduction: Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS., Methods: Podoplanin expression in human synovial tissue from 18 RA patients and nine osteoarthritis (OA) patients was assessed by immunohistochemistry and confirmed by Western blot analysis. The expression was related to markers of synoviocytes and myofibroblasts detected by using confocal immunofluoresence microscopy. Expression of podoplanin, with or without the addition of proinflammatory cytokines and growth factors, in primary human FLS was evaluated by using flow cytometry., Results: Podoplanin was highly expressed in cadherin-11-positive cells throughout the synovial lining layer in RA. The expression was most pronounced in areas with lining layer hyperplasia and high matrix metalloproteinase 9 expression, where it coincided with upregulation of α-smooth muscle actin (α-sma). The synovium in OA was predominantly podoplanin-negative. Podoplanin was expressed in 50% of cultured primary FLSs, and the expression was increased by interleukin 1β, tumour necrosis factor α and transforming growth factor β receptor 1., Conclusions: Here we show that podoplanin is highly expressed in FLSs of the invading synovial tissue in RA. The concomitant upregulation of α-sma and podoplanin in a subpopulation of FLSs indicates a myofibroblast phenotype. Proinflammatory mediators increased the podoplanin expression in cultured RA-FLS. We conclude that podoplanin might be involved in the synovial tissue transformation and increased migratory potential of activated FLSs in RA.

Objective: The aim of the study was to investigate the experience of being next of kin to an older person in the last phase of life as narrated after the older person's death., Method: Qualitative interviews were performed with the next of kin (n = 17) to people aged 75 years and older who had recently died and had received help and/or care from the municipality in the last phase of life. Eleven women and six men participated, of whom seven were spouses, nine were children, and one was a grandchild. The interviews were analysed using qualitative content analysis., Results: The experience of the next of kin could be understood as being a devoted companion during the transition toward the inevitable end, embracing the categories of living in the shadow of death; focusing on the needs of the dying person, making adjustments to everyday life; feeling the major responsibility; struggling with the health and social care system; and gaining strength from support., Significance of Results: Being next of kin to an old person at the end of life means being a devoted companion during the transition toward the inevitable end, including the feeling of bearing the major responsibility and the need to be acknowledged by professionals. This study points to the importance of having access to professional care when it is needed, to complement and support the next of kin when his or her own resources and strength falter. This also includes support to enable the next of kin to remain involved in the care of his or her loved ones, thereby fulfilling their own wishes.

Proto-oncogene survivin has recently been identified as a prognostic marker distinguishing patients with destructive rheumatoid arthritis (RA). In the present material of 132 RA patients and 82 controls, the levels of survivin correlated to urokinase (uPA) (r= 0.46), a plasminogen activator over-expressed in inflamed joints and known to exhibit potent arthritogenic properties. Here we evaluate the functional relationship between these proteins using primary synovial fibroblasts and leucocytes of RA patients, human monocytic (THP-1) and fibroblast (MRC-5) cell lines. Using inhibitors of intracellular signalling, we show that uPA and survivin share common transduction pathways in synovial fibroblasts being dependent on the activity of tyrosine kinases, phosphatidylinositide 3 kinase and mitogen effector kinase. Moreover, uPA production is significantly reduced in fibroblasts if survivin synthesis has been silenced by siRNA. Importantly, silencing of survivin in fibroblasts prevented their invasive growth in knee joints of severe combined immune deficient mice. Interaction of uPA with receptor up-regulates survivin expression in leucocytes. In turn, survivin is required for the up-regulation of uPA receptor on the cell surface. These findings indicate that survivin is an essential mediator of arthritogenic properties of uPA regulating its synthesis in synovial fibroblasts and uPAR expression in leucocytes. Close correlation between survivin and uPA levels in patients with RA supports the importance of this connection for the pathogenesis of arthritis.

Prostaglandin E(1) (PGE(1)) lowers dermal interstitial fluid pressure (IFP) in vivo and inhibits fibroblast-mediated collagen gel contraction in vitro. PDGF-BB, in contrast, stimulates contraction and normalizes IFP lowered as a result of anaphylaxis. Human diploid AG1518 fibroblasts expressed EP2, EP3 and IP prostaglandin receptors. The inhibitory effect of PGE(1) on contraction depended on cAMP. Short-term stimulation with PDGF-BB transiently induced formation of actin-containing membrane and circular ruffles and breakdown of stress fibers. PGE(1) had no effect on stress fibers nor did it modulate the effects of PDGF-BB. PGE(1) alone or in combination with PDGF-BB inhibited initial adhesion and spreading to collagen. PDGF-BB had no effect on adhesion but stimulated cell spreading. Two-dimensional gel electrophoresis and MALDI TOF analyses of SDS/Triton X-100-soluble proteins revealed changes in migration pattern of actin-binding proteins. Interestingly, PDGF-BB and PGE(1) affected both similar and different sets of actin-binding proteins. PDGF-BB and PGE(1) did not trans-modulate their respective effects on actin-binding proteins, cytoskeletal organization or initial adhesion. Our data show that PDGF-BB stimulates actin cytoskeleton dynamics, whereas PGE(1) inhibits processes dependent on cytoskeletal motor functions. We suggest that these different activities may partly explain the contrasting effects of PGE(1) and PDGF-BB on contraction and IFP.

The human endolymphatic duct (ED) with encompassing interstitial connective tissue (CT) is believed to be important for endolymph resorption and fluid pressure regulation of the inner ear. The periductal CT cells are interconnected via numerous cellular extensions, but do not form vessel structures. Here we report that the periductal CT is populated by two distinct cell phenotypes; one expressing podoplanin, a protein otherwise found on lymph endothelia and on epithelia involved in fluid fluxes, and a second expressing a fibroblast marker. A majority of the interstitial cells expressed podoplanin but not the lymphatic endothelial cell markers hyaluronan receptor (LYVE-1) or vascular endothelial growth factor receptor-3 (VEGFR-3). The fibroblast marker positive cells were found close to the ED epithelium. In the mid- and distal parts of the ED, these cells were enriched under folded epithelia. Furthermore, subepithelial CT cells were found to express activated platelet derived growth factor (PDGF)-beta receptors. Cultured CT cells from human inner ear periductal and perisaccular explant tissues were identified as fibroblasts. These cells compacted a three-dimensional collagen lattice by a process that could be promoted by PDGF-BB, a factor involved in interstitial fluid pressure regulation. Our results are compatible with the notion that the periductal CT cells are involved in the regulation of inner ear fluid pressure. By active compaction of the periductal CT and by the formation of villous structures, the CT cells could modulate fluid fluxes over the ED epithelium as well as the longitudinal flow of endolymph in the ED.

The human endolymphatic duct (ED) and sac of the inner ear have been suggested to control endolymph volume and pressure. However, the physiological mechanisms for these processes remain obscure. We investigated the organization of the periductal interstitial connective tissue cells and extracellular matrix (ECM) in four freshly fixed human EDs by transmission electron microscopy and by immunohistochemistry. The unique surgical material allowed a greatly improved structural and epitopic preservation of tissue. Periductal connective tissue cells formed frequent intercellular contacts and focally occurring electron-dense contacts to ECM structures, creating a complex tissue network. The connective tissue cells also formed contacts with the basal lamina of the ED epithelium and the bone matrix, connecting the ED with the surrounding bone of the vestibular aqueduct. The interstitial connective tissue cells were non-endothelial and non-smooth muscle fibroblastoid cells. We suggest that the ED tissue network forms a functional mechanical entity that takes part in the control of inner ear fluid pressure and endolymph resorption.

Melanomacrophages (MMs) were removed from livers of turtles of three North American families and cultured. J774 mammalian macrophages were similarly cultured and the MMs were exposed to E. coli(fluor) at approximately 2, 7, 27, and 37 degrees C. At least one third of the MMs continued to function at the low temperatures where less than 2% of the mammalian cells incorporated bacteria deeply into the cytoplasm. In most instances, when the bacteria were not internalized deeply into the cytoplasm, they became stationary just inside, or within, the cell membrane. The MMs were significantly less efficient than the mammalian cells at 37 degrees C and significantly more efficient at 2 and 7 degrees C. In general, it appears that MMs are never as efficient as mammalian macrophages under the most ideal temperatures for the cell but they are capable of functioning at reasonable levels at temperature extremes. The observations are suggestive of a genetic mechanism functioning in the MMs that is rarely expressed in J774 cells under conditions of hypothermia. MMs in vitro and probably in vivo consume bacteria, fungi, attach to helminth eggs, and consume old erythrocytes.

Acute inflammation in skin is accompanied by increased negativity of interstitial fluid pressure (PIF), which will increase capillary fluid filtration and thereby potentiate edema formation. A series of studies indicates that the connective tissue cells in rat dermis are involved in the control of PIF and mediate this response. The present study describes a novel effect of prostaglandin (PG) E1 isopropyl ester, carbaprostacyclin (PGI2 analog), and latanoprost (PGF2 alpha analog) on edema formation and PIF in parallel with their action on the fibroblast-populated collagen gel contraction assay. The prostaglandins were injected subdermally in pentobarbital-anesthetized rats. PIF was measured with a servo-controlled counterpressure system after circulatory arrest had been induced with saturated potassium chloride. Circulatory arrest was induced to limit edema formation that would raise interstitial fluid volume and thereby attenuate a possible increased negativity of PIF. PGE1 (0.91 mM) and carbaprostacyclin (1.28 mM) lowered PIF from a control value of -0.8 +/- 0.4 mmHg to -3.0 +/- 0.4 (P < 0.01) and -3.7 +/- 0.9 (P < 0.01) mmHg, respectively, within 45 min in a dose-dependent manner. Edema formation was measured in separate experiments. PGE1 and carbaprostacyclin significantly increased interstitial fluid volume (extravascular 51Cr-EDTA space) at concentrations as low as 0.1 and 1.1 microM, respectively. Latanoprost had no effect on PIF or edema formation. However, latanoprost reversed, in a dose-dependent manner, an increased negativity of PIF accompanying the anaphylactic reaction to dextran. In the gel contraction assay with human diploid fibroblasts (AG 1518), a corresponding specificity was observed where PGE1 and carbaprostacyclin effectively inhibited gel contraction although latanoprost had no effect. Thus the present data demonstrate a novel effect of prostaglandins and provide further evidence for active modulation of PIF via loose connective tissue cells.